Glycerophospholipids for the improvement of cognitive functions

ABSTRACT

The invention described herein provides a preparation comprising a non-mammalian derived mixture of serine glycerophospholipid conjugates with a specific content and specific conjugation patterns of LA, linolenic acid (alpha-linolenic acid, gamma-linolenic acid) DHA and EPA which depend on utilizing different sources of lipids, and uses of such preparations.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Ser. No. 12/215,080 which isa continuation-in-part of U.S. Ser. No. 11/414,150, filed Apr. 28, 2006,which is a CIP of U.S. Ser. No. 10/994,175, filed on Nov. 19, 2004, nowabandoned, which is a continuation of PCT International PatentApplication No. PCT/IL2004/000957, filed on Oct. 21, 2004, which claimspriority of Israeli Application No. 158552, filed on Oct. 22, 2003, thecontents of which are hereby incorporated by reference into theapplication.

FIELD OF THE INVENTION

The present invention relates to serine glycerophospholipid preparationsand their use in the improvement of cognitive functions.

BACKGROUND OF THE INVENTION

Glycerophospholipids, also referred to as phospholipids, are ubiquitousin nature, are key components of the lipid bilayer of cells, and areinvolved in cell metabolism and signaling. The hydroxyl groups of theglycerol backbone of phospholipids are substituted by a hydrophilicphosphate head and hydrophobic tail composed of non-polar fatty acids.Glycerophospholipids may be subdivided into distinct classes, based onthe nature of the polar headgroup such as for example:phosphatidylcholine (also known as PC or lecithin),phosphatidylethanolamine (PE) and phosphatidylserine (PS). In additionto serving as a primary component of cellular membranes and bindingsites for intra- and intercellular proteins, some glycerophospholipids,such as phosphatidylinositols and phosphatidic acids are eitherprecursors of, or are themselves, membrane-derived second messengers.Animal studies have shown that PS enhances neuronal membrane functionand hence slows cognitive decline, especially in the elderly [McDaniel MA et al. Nutrition 19: 957-75 (2003) and Jorissen B L et al. NutrNeurosci. 4(2):121-34 (2001)].

Many health benefits have been attributed to the consumption of certainfatty acids. For example, polyunsaturated fatty acids (PUFA) of the typeomega-3 and omega-6, have several health benefits on cardiovasculardisease, immune disorders and inflammation, renal disorders, allergies,diabetes, and cancer. Extensive clinical studies investigating theimportance of omega-3 fatty acids such as Docosahexaenoic acid (DHA) inthe brain, found that low levels of DHA are associated with depression,memory loss, dementia, and visual problems. Studies showed animprovement in the elderly brain function as blood levels of DHAincreased. Furthermore, DHA may have importance in the field of brainfunction enhancement, baby formula fortification, diabetics and cancer.

The human body does not adequately synthesize DHA. Therefore it isnecessary to obtain it from the diet. Humans obtain DHA from theirdiets, initially through the placenta, then from breast milk, and laterthrough dietary sources, such as fish, red meat, animal organ meat andeggs.

Linoleic acid (LA, C18:2, ω-6) and α-linolenic acid (ALA, C18:3, ω-3),are classified as essential fatty acids (EFA). The body cannotsynthesize them de novo, and they must therefore be obtained throughfood sources providing them “ready-made”. Both LA and ALA are needed foroptimal growth and good health. Both LA and ALA are precursors of theω-3 and ω-6 PUFA. LA is required for the synthesis of arachidonic acid(AA) (C20:4, ω-6), a key intermediate in the synthesis of eicosanoids,whereas ALA is used partly as a source of energy, and partly as aprecursor for metabolites and longer chain PUFA. Within the human bodyLA and ALA can be elongated and desaturated to other more unsaturatedfatty acids, principally AA and DHA (C22:6, ω-3), respectively.

Soybeans, egg yolk, bovine brain and fish are the major natural sourcesfor obtaining and producing phospholipids, especially PS. The type offatty acyl residues at the sn-1 and sn-2 positions in naturalphospholipids vary, and their proportion in general depends on theirsource. For example, soybean is rich with LA fatty acid (about 54%)whereas fish derived lecithin is abundant with DHA fatty acid residue.The PS extracted from animal brain tissues, similar to human brain PS,has a fatty acid content which is characterized by relatively highlevels of omega-3 moieties, compared to the levels of omega-3 found inplants, such as soy phospholipids. The bio-functionality of soybean PSin the improvement of cognitive function has been shown to be differentfrom that of human brain PS [WO 2005/037848].

SUMMARY OF THE INVENTION

The present invention provides alternative, enhanced, and cheapermethods of improving cognitive functions in a subject using a lipidpreparation conjugated with omega-3 and omega-6 fatty acids, withspecific amounts and specific conjugation patterns of LA, linolenic acid(alpha-linolenic acid, gamma-linolenic acid), DHA and eicosapentaenoyl(EPA), e.g. utilizing different sources of lipids.

The subject invention thus provides a preparation comprising anon-mammalian derived mixture of serine glycerophospholipid conjugateswherein the mixture comprises (a) linoleic acid (C18:2) conjugated to PSand (b) DHA conjugated to PS wherein the w/w % of (a)/the w/w % of (b)is from about 0.09 to about 3.6.

In another one of its aspects the invention provides a method ofimproving a condition in a subject suffering from a cognitive disease ordisorder comprising administering to a subject in need thereof apreparation of the invention.

In a further aspect the invention provides a use of a preparation of theinvention for the manufacture of a nutritional, pharmaceutical ornutraceutical composition or a functional food.

In another aspect the invention provides a preparation of the inventionfor use in a nutritional, pharmaceutical or nutraceutical composition ora functional food.

The invention further provides a nutritional, pharmaceutical ornutraceutical composition or a functional food comprising a preparationof the invention.

In another one of its aspects the invention provides a preparation ofthe invention for use in improving a condition in a subject sufferingfrom a cognitive disease or disorder.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1: shows a diagram depicting the spatial short-term memory, memoryrecall and memory recognition in adults upon administration of lipidpreparation A of the invention in comparison to administration ofplacebo.

DETAILED DESCRIPTION OF THE INVENTION

In the first aspect of the present invention there is provided apreparation comprising a non-mammalian derived mixture of serineglycerophospholipid conjugates wherein the mixture comprises (a)linoleic acid (C18:2) conjugated to PS and (b) DHA conjugated to PSwherein the w/w % of (a)/the w/w % of (b) is from about 0.09 to about3.6.

As used herein, the term “lipid” as used herein should be understood toencompass fats and fatlike compounds, which are essentially insoluble inwater and which include, but are not limited to, triglycerides, sterols,fatty acids, and so forth.

As used herein the terms “glycerophospholipid” and “phospholipids” usedinterchangeably, should be understood to encompass a lipid of thegeneral formula:

wherein the substituents, R₁ (substituent on position sn-1) and R₂(substituent on position sn-2), are independent of each other and areselected from H or an acyl group selected from saturated,mono-unsaturated and polyunsaturated fatty acids. When X is serine, i.e.—CH₂CH(COOH)NH₂, the phospholipid is referred to as serineglycerophospholipid (PS).

The sn-1 and sn-2 positions as used herein and as indicated in aboveformula, refer to the respective carbon atoms on the glycerol backbonewherein R₁ and R₂, are substituted on the corresponding acyl groups.

In the present invention, the terms “substituted” and its lingualequivalents and the term “conjugated” and its lingual equivalents areinterchangeably used and should be understood to encompass a fatty acidacyl covalently attached to the glycerophospholipid backbone of a serineglycerophospholipid of the invention. As noted above, the fatty acid maybe attached to the sn-1 and/or sn-2 positions.

As used herein, the term “fatty acid” should be understood to encompassa carboxylic acid with a long unbranched aliphatic tail (chain), whichis either saturated or unsaturated having one unsaturated bond(mono-unsaturated fatty acids) or two or more unsaturated bonds(poly-unsaturated fatty acids). When referring to a “fatty acid acyl” itshould be understood to encompass an —C(═O)—R radical wherein R is along unbranched aliphatic tail, which is either saturated or unsaturatedhaving one unsaturated bond (mono-unsaturated fatty acids) or two ormore unsaturated bonds (poly-unsaturated fatty acids).

Non-limiting examples of saturated fatty acids include: Butyric acid(Butanoic acid, C4:0), Caproicacid (Hexanoic acid, C6:0), Caprylic acid(Octanoic acid, C8:0), Capric acid (Decanoic acid, C10:0), Lauric acid(Dodecanoic acid, C12:0), Myristic acid (Tetradecanoic acid, C14:0),Palmitic acid (Hexadecanoic acid, C16:0), Stearic acid (Octadecanoicacid, C18:0), Arachidic acid (Eicosanoic acid, C20:0), Behenic acid(Docosanoic acid C22:0).

Non-limiting examples of unsaturated fatty acids include: Myristoleicacid (C14:1, ω-5), Palmitoleic acid (C16:1, ω-7), Oleic acid (C18:1,ω-9), Linoleic acid (C18:2, ω-6), Linolenic acid (C18:3)[Alpha-linolenic acid (C18:3, ω-3), Gamma-linolenic acid (C18:3, ω-6)],Eicosenoic acid (C20:1, ω-9), Arachidonic acid (C20:4, ω-6),Eicosapentaenoic acid (C20:5, ω-3), Erucic acid (C22:1, ω-9),Docosapentanoic acid (C22:5, ω-3) and Docosahexaenoic acid (C22:6, ω-3),Nervonic acid (C24:1, ω-9).

When referring to a “. . . [fatty acid] conjugated to PS . . . ”, itshould be understood to encompass a PS wherein a fatty acid acyl isconjugated at position sn-1 and/or position sn-2 of the phospholipidbackbone (through the glycerol oxygen atom). In one embodiment a fattyacid is conjugated at position sn-1, and position sn-2 is eitherunsubstituted (e.g. having a hydrogen atom on the glycerol oxygen) orsubstituted with an acyl group selected from saturated, mono-unsaturatedand polyunsaturated fatty acids, which may be the same or different fromthe substitution on position sn-1. In another embodiment a fatty acid isconjugated at position sn-2 and position sn-1 is either unsubstituted(e.g. having a hydrogen atom on the glycerol oxygen) or substituted withan acyl group selected from saturated, mono-unsaturated andpolyunsaturated fatty acids, which may be the same or different from thesubstitution on position sn-2.

A preparation of the invention typically comprises a mixture of two ormore serine glycerophospholipid conjugates of the invention, havingfatty acid conjugation patterns as disclosed herein.

When referring to a w/w % of a fatty acid conjugated to PS in apreparation of the invention, it should be understood that the w/w % ofsaid fatty acid which is conjugated to PS is calculated relative to theweight of the total fatty acids conjugated to PS in the preparation.

In one embodiment, the mixture of serine glycerophospholipid conjugatesconstitutes at least 10% w/w of the preparation. In another embodimentthe mixture of serine glycerophospholipid conjugates constitutes atleast 20% w/w of the preparation. In a further embodiment the mixture ofserine glycerophospholipid conjugates constitutes at least 40% w/w ofthe preparation. In yet another embodiment the mixture of serineglycerophospholipid conjugates constitutes at least 50% w/w of thepreparation. In a further embodiment the mixture of serineglycerophospholipid conjugates constitutes at least 54% w/w of thepreparation.

It should be noted that the preparation of the invention may alsocomprise other phospholipids, such as phosphatidylcholine (PC),phosphatidylethanolamine (PE), phosphatidyl-inositol (PI),phosphatidylglycerol (PG) and phosphatidic acid (PA), to which fattyacid acyls are covalently attached (bonded) at either or both of thesn-1 or sn-2 positions of the glycerol moiety of the phospholipid. Thefatty acid conjugation profile of any of the above-noted polar lipidsmay be the same as, or different from, the fatty acid conjugationprofile of PS, as disclosed herein.

The terms “[PS] fatty acid conjugation pattern” and “[PS] fatty acidconjugation profile” are interchangeably used herein and refer to aparticular content of specific fatty acids conjugated to PS and theirposition of substitution on the PS glycerol backbone.

In one embodiment, a preparation of the invention further comprises (c)linolenic acid (C18:3) conjugated to PS and (d) DHA conjugated to PSwherein the w/w % of (c)/w/w % of (d) is from about 0.01 to about 0.3.

In another embodiment, a preparation of the invention further comprises(e) linoleic acid (C18:2) conjugated to PS and (f) EPA conjugated to PSwherein the w/w % of (e)/w/w % of (f) is from about 0.23 to about 9.4.

In a further embodiment, a preparation of the invention furthercomprises (g) linolenic acid (C18:3) conjugated to PS and (h) EPAconjugated to PS wherein the w/w % of (g)/w/w % of (h) is from about0.02 to about 0.8.

The preparation of the present invention may be prepared throughenzymatic, chemical or molecular biology methods. Briefly, PS can beenriched with omega-3 or omega-6 fatty acids by enzymatic processes,e.g. enrichment of a natural phospholipid/lecithin with omega-3/omega-6fatty acids by enzymatic transesterification/esterification followed bytransformation of the head group to serine (using PLD enzymes) to obtaina PS-omega-3/omega-6 conjugate. Another enzymatic pathway is to obtain aphospholipid source which is naturally rich in omega-3 acids, such asmarine-derived lecithin (e.g. hill, fish or algae) or eggsphospholipids, and transform their head groups to serine. It is to benoted that the fatty acid content of the PS obtained by this method hasan omega-3 content which is predetermined by the source of choice (fish,krill, algae, soy etc.). Such methods have been described in WO2005/038037.

The PS preparation of the present invention can also be prepared bychemical transesterification/esterification methods that will enrich thesn-1 and 2 positions with omega-3 or omega-6 acyl residues. Such methodsof preparation of PS-omega-3 and PS-omega-6 have been described in WO2005/038037.

Alternatively, the PS preparation of the present invention can beprepared by GMO (genetically modified. organisms)/biotechnology methods,for example, providing phospholipids-producing organisms with omega-3 oromega-6 fatty acids to obtain phospholipids enriched with omega-3 oromega-6 PS. It may be preferred to use genetically engineered plants ormicroorganisms, to avoid use of animal sources.

Thus, a mixture of serine glycerophospholipid conjugates of theinvention is prepared from a natural, synthetic or semi-synthetic sourceor any combinations thereof. In an embodiment of the present invention,said natural source is derived from any one of plant (such as forexample soy and algae), non-mammalian animal (such as for example krill,fish (such as for example Herring and blue Whiting)), or microorganism(such as for example bacteria) source or any combinations thereof. PSfrom different sources have different fatty acid conjugation patterns.For example, soy lecithin contains higher levels of linoleic acidconjugated to PS as compared with marine lecithin which contains higherlevels of DHA conjugated to PS.

In yet a further embodiment, the production of said lipid preparationinvolves an enzymatic catalysis.

PS extracted from bovine cortex (BC-PS) is associated with a positiveeffect on brain function and cognitive abilities, while PS derived fromsoybean (SB-PS) obtained inconclusive results regarding its ability toimprove cognitive functions. Without being bound by theory, thisdifference in efficacy was attributed to the different fatty acidcomposition of the two PS sources. While BC-PS has a relatively high DHAcontent and low LA content, SB-PS is enriched with LA and has no DHAattached to its backbone. It is thus assumed that the PS compositionswith low ratio of LA/DHA will serve as better cognitive enhancers.

The present invention surprisingly provides specific preparations of PSwith LA/DHA ratios of 0.09-3.6 which are as effective, and in some caseseven more effective, than PS preparations with lower LA/DHA ratios (moreDHA), in their ability to enhance cognitive functions.

The subject invention envisages that the use of a preparation of theinvention comprising a mixture of serine glycerophospholipids withspecific fatty acid conjugation patterns, which may be derived fromdistinct sources or may be prepared synthetically, results in similar orimproved cognitive functions as compared to lipid preparations derivedfrom a single source or prepared to mimic the fatty acid content of alipid preparation derived from a single source. For example, a lipidpreparation comprising PS conjugated with more LA than purelymarine-derived lipid preparations, have a similar or improved effect oncognitive functions as compared to either plant derived (such as soy)lipids on the one hand or marine derived (such as fish) lipids on theother. Such lipid preparations, derived from more than one source orprepared synthetically to mimic the fatty acid content of lipidpreparations derived from more than one source, are also cheaper toprepare than purely marine derived lipid preparations.

The preparation of the invention may be in the form of fluid oil,powder, granules, wax, paste, oil or aqueous emulsion, and any otherform that will enable its use in the target applications.

In another one of its aspects the invention provides a use of apreparation of the invention, for the manufacture of a nutritional,pharmaceutical or nutraceutical composition or a functional food.

In a further aspect the invention provides a preparation of theinvention, for use in a nutritional, pharmaceutical or nutraceuticalcomposition or a functional food.

In yet a further aspect the invention provides a nutritional,pharmaceutical or nutraceutical composition or a functional foodcomprising a preparation of the invention.

A nutritional composition as used herein can be any nutritionalcomposition including, but not limited to, human milk fat substitute,infant formula, dairy product, milk powder, drinks, ice-cream, biscuit,soy product, bakery, pastry and bread, sauce, soup, prepared food,frozen food, condiment, confectionary, oils and fat, margarine, spread,filling, cereal, instant product, infant food, toddler food, bar, snack,candy and chocolate product.

The term “infant formula” as used herein encompasses infant formulas(for newborn to 6 months old infants), follow-up formulas (for 6-12months old babies) and growing up formulas (for 1-3 years old children).

A functional food as used herein can be any functional food, including,but not limited to, dairy product, ice-cream, biscuit, soy product,bakery, pastry, cakes and bread, instant product, sauce, soup, preparedfood, frozen food, condiment, confectionary, oils and fat, margarine,spread, filling, cereal, instant product, drinks and shake, infant food,bar, snack, candy and chocolate product.

A nutraceutical composition as used herein can be any nutraceutical,which can be any substance that may be considered a food or part of afood and provides medical or health benefits, including the preventionand treatment of diseases or disorders. Such nutraceutical compositionsinclude, but are not limited to, a food additive, a food supplement, adietary supplement, genetically engineered foods such as for examplevegetables, herbal products, and processed foods such as cereals, soupsand beverages and stimulant functional food, medical food andpharmafood. Dietary supplements may be delivered in the form of soft gelcapsules, tablets, syrups, and other known dietary supplement deliverysystems.

In an embodiment of the invention, the pharmaceutical or nutraceuticalcompositions are in a dosage delivery form.

Suitable routes of administration for the compositions of the subjectinvention are oral, buccal, sublingual administration, administrationvia a feeding tube, topical, transdermal, or parenteral (includingsubcutaneous, intramuscular, intravenous and intradermal)administration. In one embodiment, the compounds are administeredorally.

The exact dose and regimen of administration of the composition willnecessarily be dependent upon the therapeutic effect to be achieved(e.g. improving a condition in a subject suffering from a cognitivedisease or disorder) and may vary with the particular formula, the routeof administration, and the age and condition of the individual subjectto whom the composition is to be administered.

The present invention thus also provides pharmaceutical compositions ofthe invention in admixture with (pharmaceutically) acceptableauxiliaries, and optionally other therapeutic agents. The auxiliariesmust be “acceptable” in the sense of being compatible with the otheringredients of the composition and not deleterious to the recipientsthereof.

In one embodiment, a pharmaceutical composition of the invention furthercomprises at least one pharmaceutically active agent.

The pharmaceutical and nutraceutical compositions may be prepared by anymethod well known in the art of pharmacy. Such methods include the stepof bringing in association the ingredients with any auxiliary agent. Theauxiliary agent(s), also named accessory ingredient(s), include thoseconventional in the art, such as carriers, fillers, binders, diluents,dessicants, disintegrants, lubricants, colorants, flavoring agents,anti-oxidants, and wetting agents.

The pharmaceutical and nutraceutical compositions of the invention mayfurther comprise edible fibers, aroma, taste ingredients, andingredients that control physical and organoleptic properties.

Pharmaceutical compositions suitable for oral administration may bepresented as discrete dosage units such as pills, tablets, pellets,dragees, or capsules, or as a powder or granules, or as a solution,suspension or elixir.

For parenteral administration, suitable compositions include aqueous andnon-aqueous sterile injection. The compositions may be presented inunit-dose or multi-dose containers, for example sealed vials andampoules, and may be stored in a freeze-dried (lyophilised) conditionrequiring only the addition of sterile liquid carrier, for examplewater, prior to use. For transdermal administration, e.g. gels, patchesor sprays can be contemplated.

The compositions may be presented in unit-dose or multi-dose containers,for example sealed vials and ampoules, and may be stored in afreeze-dried (lyophilised) condition requiring only the addition ofsterile liquid carrier, for example water, prior to use.

The invention further provides a commercial package and/or kit forpreparing a composition of the invention such as an edible fat source orfood article in accordance with the invention comprising (a) a fatsource; (b) optionally at least one of edible physiologically acceptableprotein, carbohydrate, vitamin, mineral, amino acid, nucleotide andactive or non-active additive; (c) optionally at least one ediblephysiologically acceptable carrier or diluent for carrying theconstituent/s defined in (a) and (b); (d) means and receptacles foradmixing the constituents defined in (a), (b) and/or (c); and (e)instructions for use such as, but not limited to terms of storage,instructions for preparation of the fat source or food article foradministration, required dilutions, dosages, frequency of administrationand the like.

A commercial package or kit in accordance with the invention may alsocontain a fat source of the invention in a ready-to-use form, togetherwith instructions for use. Dosages are usually determined according toage, weight, sex and condition of the subject, in accordance with goodmedical practice known to the attending physician and other medicalpersonnel.

In another one of its aspects the invention provides a method ofimproving a condition in a subject suffering from a cognitive disease ordisorder comprising administering to a subject in need thereof apreparation of the invention.

The invention further provides a use of a preparation of the inventionfor the manufacture of a nutritional, pharmaceutical or nutraceuticalcomposition or a functional food for improving a condition in a subjectsuffering from a cognitive disease or disorder.

In another one of its aspects the invention provides a preparation ofthe invention for use in improving a condition in a subject sufferingfrom a cognitive disease or disorder.

The term “cognitive disease or disorder” as used herein should beunderstood to encompass any cognitive disease or disorder. Non-limitingexamples of such a cognitive disease or disorder are Attention DeficitDisorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD),dyslexia, age-associated memory impairment and learning disorders,amnesia, mild cognitive impairment, cognitively impaired non-demented,pre-Alzheimer's disease, Alzheimer's disease, Parkinson's disease,pre-dementia syndrome, dementia, age related cognitive decline,cognitive deterioration, moderate mental impairment, mentaldeterioration as a result of aging, conditions that influence theintensity of brain waves and/or brain glucose utilization, stress,anxiety, depression, behavior disorders, concentration and attentionimpairment, mood deterioration, general cognitive and mental well being,neurodegenerative disorders, hormonal disorders or any combinationsthereof. In a specific embodiment, the cognitive disorder is memoryimpairment.

The term “improving a condition in a subject suffering from a cognitivedisease or a cognitive disorder” as used herein should be understood toencompass: ameliorating undesired symptoms associated with a disease,disorder, or pathological condition; preventing manifestation ofsymptoms before they occur; slowing down progression of a disease ordisorder; slowing down deterioration of a disease or disorder; slowingdown irreversible damage caused in a progressive (or chronic) stage of adisease or disorder; delaying onset of a (progressive) disease ordisorder; reducing severity of a disease or disorder; curing a diseaseor disorder; preventing a disease or disorder from occurring altogether(for example in an individual generally prone to the disease) or acombination of any of the above. For example, in a subject sufferingfrom memory impairment, for example as a result of Alzheimer's Disease,symptoms including deterioration of spatial short-term memory, memoryrecall and/or memory recognition, focused and sustained attention,learning, executive functions and/or mental flexibility are improved byuse of a lipid preparation of the invention.

In one embodiment of the invention a cognitive disease or disorder isselected from the group consisting of Attention Deficit Disorder,Attention Deficit Hyperactivity Disorder, dyslexia, age-associatedmemory impairment and learning disorders, amnesia, mild cognitiveimpairment, cognitively impaired non-demented, pre-Alzheimer's disease,Alzheimer's disease, Parkinson' disease, pre-dementia syndrome,dementia, age related cognitive decline, cognitive deterioration,moderate mental impairment, mental deterioration due to aging,conditions that influence the intensity of brain waves and/or brainglucose utilization, stress, anxiety, depression, behavior disorders,concentration and attention impairment, mood deterioration, generalcognitive and mental well being, neurodegenerative disorders, hormonaldisorders and any combinations thereof.

It will be appreciated that a composition (whether pharmaceutical,nutraceutical, nutritional, etc) or product (e.g. functional food) ofthe invention may be combined with other treatment methods known in theart (i.e., combination therapy). Thus, treatment of cognitive diseasesor disorders using a composition or product of the invention may becombined with conventional drugs for the treatment of cognitive diseasesor disorders.

Non limiting examples of drugs indicated for the treatment of cognitivediseases or disorders include Acetylcholine esterase inhibitors (such asfor example aricept (donepezil), exelon (rivastigmine), reminyl(galantamine), N-methyl-D-aspartate (NMDA) receptor antagonists (such asfor example AP5 (APV, R-2-amino-5-phosphonopentanoate), AP7(2-amino-7-phosphonoheptanoic acid), CPPene(3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid),Amantadine: Dextromethorphan, Dextrorphan, Ibogaine, Ketamine,Memantine, Nitrous oxide, Phencyclidine, Riluzole, Tiletamine,Aptiganel, HU-211, HU-210, Remacimide, 1-Aminocyclopropanecarboxylicacid, DCKA (5,7-dichlorokynurenic acid), Kynurenic acid, and Lacosamide.

A composition or product of the invention may also be administered inconjunction with other compounds, including, but not limited to folicacid, vitamins, minerals, amino acids, nucleotides, antioxidants and soforth.

Disclosed and described, it is to be understood that this invention isnot limited to the particular examples, process steps, and materialsdisclosed herein as such process steps and materials may vary somewhat.It is also to be understood that the terminology used herein is used forthe purpose of describing particular embodiments only and not intendedto be limiting since the scope of the present invention will be limitedonly by the appended claims and equivalents thereof.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a”, “an” and “the” include plural referentsunless the content clearly dictates otherwise.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

The following Examples are representative of techniques employed by theinventors in carrying out aspects of the present invention. It should beappreciated that while these techniques are exemplary of preferredembodiments for the practice of the invention, those of skill in theart, in light of the present disclosure, will recognize that numerousmodifications can be made without departing from the spirit and intendedscope of the invention.

EXAMPLES Example 1

Method of Preparing a Lipid Preparation of the Invention

Lipid preparations A, A1, A2, C, D, F, G, H, I, J, K, L, M, and N areprepared as follows:

Marine lecithin produced by an extraction process from biomass derivedfrom fish (mainly Herring and blue Whiting) was dissolved in organicsolvents and allowed to react with an aqueous solution containingL-serine, CaCl₂, phospholipase D (PLD) and acetate buffer at pH of 5.6.The resulting PS preparation was purified by removal of the water phase,evaporation of the organic solvents and further purification stages. Theresulted powder contained 44% PS and 31% DHA from PS fatty acids.

PC enriched soybean lecithin was reacted with aqueous medium containingL-serine, CaCl₂, PLD and acetate buffer at pH of 5.6. The resulting PSpreparation was washed from water soluble material (salts, serine etc.)and further purified. The resulting powder contained 67.4% PS.

The powder obtained from the marine lecithin origin, and the powderobtained from the soybean lecithin origin, were mixed together in ratiosas described in Table 5.

Alternatively, lipid preparations A, A1, A2, C, D, F, G, H, I, J, K, L,M, and N are prepared as follows:

120 gram of marine lecithin and 60 gram PC enriched soybean lecithin aredissolved together in organic solvents in a 3 liter glass lab reactor.The described organic phase is allowed to react with an aqueous solutioncontaining L-serine, CaCl₂, PLD and acetate buffer at pH of 5.6. Theresulted PS is purified by removal of the water phase, evaporation ofthe organic solvents and further purification stages.

Lipid Preparation B was Prepared as Follows:

Marine lecithin produced by an extraction process from biomass derivedfrom fish (mainly Herring and blue Whiting) was dissolved in organicsolvents and allowed to react with an aqueous solution containingL-serine, CaCl₂, phospholipase D (PLD) and acetate buffer at pH of 5.6.The resulting PS preparation was purified by removal of the water phase,evaporation of the organic solvents and further purification stages. Theresulting powder contained 44% PS and 31% DHA from PS fatty acids.

Lipid Preparation E was Prepared as Follows:

PC enriched soybean lecithin was reacted to PS in aqueous medium thatcontaining L-serine, CaCl₂, PLD and acetate buffer at pH of 5.6. Theresulting PS was washed from water soluble material (salts, serine etc.)and further purified. The resulting powder contained 67% PS.

Table 5 provides the fatty acid ratio and the source ratio ofpreparations A, B, C, D, E and F of the examples below. The fatty acidand phospholipid content of each of these lipid preparations is furtherspecified in Tables 2 and 3 below.

Lipid preparations A, A1 and A2 are different batches of the samepreparation.

Lipid preparations A, A1 and A2 have a ratio between linoleic acid(C18:2) (LA) conjugated to PS (w/w %) and Docosahexaenoic acid (DHA)conjugated to PS (w/w %) of about 0.9-1.4; have a ratio betweenlinolenic acid (18:3) conjugated to PS (w/w %) and DHA conjugated to PS(w/w %) of about 0.08-0.13; have a ratio between LA (18:2) conjugated toPS (w/w %) and EPA conjugated to PS (w/w %) of about 2.3-3.5; and have aratio between linolenic acid (18:3) conjugated to PS (w/w %) and EPAconjugated to PS (w/w %) of about 0.2-0.3, wherein the total DHAconjugated to PS constitutes about 19-22% w/w of total fatty acidsconjugated to PS.

Lipid preparation B (100% marine-derived) has a ratio between linoleicacid (LA) (C18:2) conjugated to PS (w/w %) and DHA conjugated to PS (w/w%) of at most about 0.02; has a ratio between Linolenic acid (18:3)conjugated to PS (w/w %) and DHA conjugated to PS (w/w %) of at mostabout 0.02; has a ratio between LA (18:2) conjugated to PS (w/w %) andEPA conjugated to PS (w/w %) of at most about 0.05; and has a ratiobetween linolenic acid (18:3) conjugated to PS (w/w %) and EPAconjugated to PS (w/w %) of at most about 0.05; wherein the total DHAconjugated to PS constitutes about 31% w/w of total fatty acidsconjugated to PS.

Lipid preparation C has a ratio between linoleic acid (LA) (C18:2)conjugated to PS (w/w %) and DHA conjugated to PS (w/w %) of about 0.1;has a ratio between linolenic acid (18:3) conjugated to PS (w/w %) andDHA conjugated to PS (w/w %) of about 0.01; has a ratio between LA(18:2) conjugated to PS (w/w %) and EPA conjugated to PS (w/w %) ofabout 0.23; and has a ratio between Linolenic acid (18:3) conjugated toPS (w/w %) and EPA conjugated to PS (w/w %) of about 0.02; wherein thetotal DHA conjugated to PS constitutes about 30% w/w of total fattyacids conjugated to PS.

Lipid preparation D has a ratio between linoleic acid (LA) (C18:2)conjugated to PS (w/w %) and DHA conjugated to PS (w/w %) of about 3.6;has a ratio between Linolenic acid (18:3) conjugated to PS (w/w %) andDHA conjugated to PS (w/w %) of about 0.3; has a ratio between LA (18:2)conjugated to PS (w/w %) and EPA conjugated to PS (w/w %) of about 9.4;and has a ratio between Linolenic acid (18:3) conjugated to PS (w/w %)and DHA conjugated to PS (w/w %) of about 0.8; wherein the total DHAconjugated to PS constitutes about 11% w/w of total fatty acidsconjugated to PS.

Lipid preparation E (100% soy-derived) has a ratio between linoleic acid(LA) (C18:2) conjugated to PS (w/w %) and DHA conjugated to PS (w/w %)of above 100; has a ratio between Linolenic acid (18:3) conjugated to PS(w/w %) and DHA conjugated to PS (w/w %) of above 10; has a ratiobetween LA (18:2) conjugated to PS (w/w %) and EPA conjugated to PS (w/w%) of above 100; and has a ratio between Linolenic acid (18:3)conjugated to PS (w/w %) and EPA conjugated to PS (w/w %) of above 10,with practically no DHA.

Lipid preparation F has a ratio between linoleic acid (LA) (C18:2)conjugated to PS (w/w %) and DHA conjugated to PS (w/w %) of about 9;has a ratio between Linolenic acid (18:3) conjugated to PS (w/w %)andDHA conjugated to PS (w/w %) of about 0.7; has a ratio between LA (18:2)conjugated to PS (w/w %) and EPA conjugated to PS (w/w %) of about 23;and has a ratio between Linolenic acid (18:3) conjugated to PS (w/w %)and DHA conjugated to PS (w/w %) of about 1.8; wherein the total DHAconjugated to PS constitutes about 5.6% w/w of total fatty acidsconjugated to PS.

In order to avoid hyper-inflammatory situations, it is preferable tosupplement subjects with omega-3 fatty acids in a balanced ratio withomega-6 fatty acids. Omega 3 fatty acids increase bleeding time,decrease platelet aggregation, blood viscosity, and fibrinogen; andincrease erythrocyte deformability; thus decreasing the tendency tothrombus formation. Table 8 shows the ratio between omega 6 and omega 3fatty acids conjugated to PS and shows that preparations A, C and D havebalanced ratios whereas a ratio of <0.01 (as in preparation B) or >10(as in preparation E) may be considered not balanced.

It is to be understood that the subject invention is not limited topreparations A, C and D. Other preparations (G-N) comprising for example50%, 55%, 60%, 65%, 70%, 80%, 85%, and 90% marine material (i.e. 50%,45%, 40%, 35%, 30%, 20%, 15%, and 10% soy material) are also envisaged(Table 9).

Example 2

Efficacy of Lipid Preparation A

I. The efficacy of lipid preparation A (prepared according to Example 1above), was investigated in a single-center, double-blind, randomized,placebo-controlled ˜3 months trial in elderly with impaired cognitiveperformance.

According to the study design, 160 subjects were intended to berandomized following screening to one of two treatment groups, 80subjects in each treatment group:

(a) 1 capsule containing 200 mg of lipid preparation A, was administeredthree (3) times daily with meals.

(b) placebo—1 capsule containing 260-270 mg cellulose was administeredthree (3) times daily with meals.

The capsules containing lipid preparation A and the placebo capsuleswere of identical appearance, taste and smell.

Memory functions of 15 subjects who received preparation A treatment and18 subjects who received placebo capsules were tested using NexAdecomputerized neuropsychological assessment software (NexSig NeurologicalExamination Technologies Ltd, Israel) at baseline and following ˜3treatment months.

The computerized neuropsychological assessment software consisted ofseven separate tasks including: symbol spotting, pattern identification,pattern recall, digit-symbol substitution, digits span forward, digitsspan backward and delayed pattern recall. Based on the results obtainedin the single tasks, eight cognitive composite scores were calculatedincluding focused attention (the ability to respond discretely tospecific visual auditory or tactile stimuli), sustained attention (theability to maintain a consistent behavioral response during continuousand repetitive activity), memory recognition (the ability to identifypreviously stored information), memory recall (involves digging into thememory and bringing back information on a stimulus/response basis),visuospatial learning, spatial short term memory (a memory system thatstores spatial information for a few seconds so that it can be used inthe service of ongoing cognitive tasks), executive functions and mentalflexibility. A final score which considered all of the cognitivecomposite scores was calculated as well. The software presenteddifferent, though equivalent, forms of the tests, which allowed repeatedtesting. All tasks were computer-controlled and no previous experiencewith computers or typing was required (Aharonson V, Korczyn A D: Humancomputer interaction in the administration and analysis ofneuropsychological tests. elsevier science publishers B.V. 2004;73:43-53).

Results

FIG. 1 indicates that lipid preparation A improved memory parametersfollowing ˜3 months treatment period.

FIG. 1 demonstrates three of the memory parameters that were tested:memory recall, memory recognition and spatial short term memory. Memoryrecall and recognition is a “process” used to get information back outof our memory. Memory recall involves digging into the memory andbringing back information on a stimulus/response basis, and memoryrecognition indicates the ability to identify previously storedinformation.

Spatial short term memory is a memory system that stores spatialinformation for a few seconds so that it can be used in the service ofongoing cognitive tasks. The results presented in FIG. 1 show that lipidpreparation A improved cognitive performance of learning and memoryabilities in comparison with placebo.

Thus, lipid preparation A improved mild cognitive impairment andage-associated memory impairment.

II. The efficacy of lipid preparation A (prepared according to Example 1above), was further investigated in a single center, 3 months trial, in52 elderly (age ≧60) with impaired cognitive performance.

Subjects received one capsule containing 200 mg of lipid preparation A(containing 100 mg PS) three times a day.

Memory functions of the subjects were tested at baseline and following 3treatment months using the following test procedures:

-   -   1. NexAde™ computerized cognitive assessment tool (as described        above).    -   2. Rey-Auditory Verbal Learning Test (AVLT) (Rey A: L′Examen        Clinique en Psychologie Paris: Press Universitaire de France        1964)

This test consisted of a list of 15 common nouns, which were read to thesubject in five consecutive trials (trials 1 through 5); each readingwas followed by a free recall task. In trial 6, an interference list of15 new common nouns was presented, followed by free recall of these newnouns. In trial 7, without additional reading, subjects were again askedto recall the first list. Twenty minutes later, and again without anadditional reading, subjects were asked to recall again the first list(trial 8). Five different scores were derived from the test; immediatememory recall (trial 1 score), total immediate recall (sum of scores oftrial 1 and 6), best learning (trial 5), verbal total learning (sum ofscores of trial 1 through 5) and delayed memory recall (trial 8).

Results

Table 1 indicates that lipid preparation A significantly improved thefinal score of the computerized cognitive assessment tool. This score isan adjusted calculation that sums the different composite scores. Table1 demonstrates individual tests (digits recall forward and backward) andspecific composite scores (focused attention, memory recall and memoryrecognition) that were significantly improved. It is concluded thatlipid composition A significantly improved numerous cognitive parameterssuch as attention, memory and learning.

TABLE 1 The effect of Lipid preparation A on the computerized cognitiveassessment tool parameters Tested parameters Mean change from baseline ±SE p* Digits recall forward 5.44 ± 2.54 0.076 Digits recall backward2.98 ± 2.38 0.001 Focused attention 3.81 ± 1.65 0.003 Memory recognition8.29 ± 2.06 0.032 Memory recall 5.17 ± 1.46 0.025 Final score 5.12 ±1.77 0.002 *Based on two-side students' T-test for dependent samples.

Table 2 indicates that lipid preparation A improved the differentparameters of Rey-AVLT procedure, and thus further confirms thecognitive enhancement properties of the preparation. Specifically, lipidcomposition A significantly improved immediate and delayed memoryrecall, best learning, total learning and total immediate recall.

TABLE 2 Effect of lipid preparation A on Rey-AVLT parameters Testedparameters Mean change from baseline ± SE p* Immediate memory recall1.87 ± 0.26 <0.001 Best learning 0.65 ± 0.28 <0.001 Delayed memoryrecall 1.10 ± 0.32 <0.001 Verbal total learning 6.17 ± 0.94 <0.001 Totalimmediate recall 2.19 ± 0.43 <0.001 *Based on two-side students' T-testfor dependent samples.

In conclusion, lipid preparation A improved mild cognitive impairmentand age-associated memory impairment.

Example 3

Efficacy of Lipid Preparations B, C, D, E, and F

All trials described tested the same population (elderly subjects withimpaired cognitive performance) and utilized the same cognitiveassessment tools.

Efficacy of Lipid Preparation B

The efficacy of lipid preparation B (prepared according to Example 1above) was investigated in a single-center, open label, ˜3 months trialin 16 elderly (age≧60) with impaired cognitive performance.

1 capsule containing 227 mg of lipid preparation B (containing 100 mgPS) was administered three (3) times daily with meals.

Memory functions of the subjects were tested at baseline and following 3treatment months using computerized cognitive assessment toolessentially as described in Example 2 above.

Results

Table 3 indicates that lipid preparation B improved the final score ofthe computerized cognitive assessment tool. Although the improvement didnot reach statistical significance, its magnitude was comparable to thatfollowing lipid preparation A consumption (see Table 1). An improvementwas also detected in individual tests (digits recall forward andbackward) and specific composite scores (spatial short term memory,focused attention, memory recall and memory recognition) that wereimproved by lipid preparation B. Again, the magnitude of the effect wascomparable to that following treatment with preparation A (see Table 1),but the improvement didn't always reach statistical significance. It isthus concluded that lipid preparation B improved several cognitiveparameters similarly to lipid preparation A, however, since theimprovement did not always reach statistical significance, it seems thatlipid preparation A has an advantage over lipid preparation B inimproving cognitive skills and treating mild cognitive impairment andage associated memory decline. These results are surprising since lipidpreparation B has a lower LA/DHA ratio (more DHA) in comparison withlipid preparation A.

TABLE 3 Effect of lipid preparation B on the computerized cognitiveassessment tool parameters Tested parameters Mean change from baseline ±SE p* Digits recall forward 4.63 ± 5.70 0.870 Digits recall backward0.88 ± 4.94 0.987 Focused attention 3.25 ± 3.21 0.070 Memory recognition2.75 ± 2.20 0.033 Memory recall 5.94 ± 2.79 0.032 Final score 5.05 ±2.67 0.133 *Based on two-side students' T-test for dependent samples.

Efficacy of Lipid Preparation C

The efficacy of lipid preparation C is investigated in a single-center,open label, ˜3 months trial in 8 elderly with impaired cognitiveperformance.

1 capsule containing 222 mg lipid preparation C (containing 100 mg PS)is administered three (3) times daily with meals.

Memory functions of the subjects are tested using computerized cognitiveassessment tool and Rey-AVLT essentially as described in Example 2.

Results

Lipid preparation C improves memory recall, memory recognition,attention, concentration, learning and spatial short term memoryfollowing ˜3 months treatment period. The improvement of all parameterstested is similar to the improvement following ˜3 treatment months withlipid preparation A (Example 2) and similar to, or better than, theimprovement following ˜3 treatment months with lipid preparation B.

Efficacy of Lipid Preparation D

The efficacy of lipid preparation D is investigated in a single-center,open label, ˜3 months trial in 8 elderly with impaired cognitiveperformance.

1 capsule containing 176 mg of lipid preparation D (containing 100 mgPS) is administered three (3) times daily with meals.

Memory functions of the subjects are tested using computerized cognitiveassessment tool and Rey-AVLT essentially as described in Example 2.

Results

Lipid preparation D improves memory recall, memory recognition,attention, concentration, learning and spatial short term memoryfollowing ˜3 months treatment period. The improvement of all parameterstested is similar to the improvement following ˜3 treatment months withlipid preparation A (Example 2) and C, and similar to or better than theimprovement following ˜3 treatment months with lipid preparation B.

Efficacy of Lipid Preparation E

The efficacy of lipid preparation E (prepared according to Example 1above) was investigated in a single-center, open label, ˜3 months trialin 24 elderly (age≧60) with impaired cognitive performance.

1 capsule containing 150 mg of lipid preparation E (containing 100 mgPS) was administered three (3) times daily with meals.

Memory functions of the subjects were tested at baseline and following 3treatment months using Rey-AVLT procedure essentially as described inExample 2.

Results

Table 4 indicates that lipid preparation E, as lipid preparation A,improved the parameters tested in Rey-AVLT procedure. However, incomparison with lipid preparation A, the magnitude of the effect wasconsiderably smaller. Comparison between lipid preparation A and Erevealed a statistical significant difference, in favor of preparationA, between the two treatments in immediate recall (p=0.05) and totalimmediate recall (p=0.03) and a trend in the total learning score(p=0.13). This difference reflects the superiority of lipid preparationA over lipid preparation E in the treatment of cognitive deterioration.

TABLE 4 Effect of lipid preparation E on Rey-AVLT parameters Testedparameters Mean change from baseline ± SE P* Immediate memory recall0.96 ± 0.36 0.032 Best learning 0.42 ± 0.53 0.002 Delayed memory recall0.71 ± 0.50 <0.001 Verbal total learning 3.54 ± 1.47 <0.001 Totalimmediate recall 0.58 ± 0.48 0.001 *Based on two-side students' T-testfor dependent samples.

In addition, memory functions of the subjects are tested at baseline andfollowing 3 treatment months using the computerized cognitive assessmenttool essentially as described in Example 2.

Results

Lipid preparation E tends to improve memory recall, memory recognition,attention, concentration, learning and spatial short term memory only toa minor extent following ˜3 months treatment period. The improvement ofall parameters tested is lower than the improvement following ˜3treatment months with any of the lipid preparations A (Example 2), B, Cand D.

Efficacy of Lipid Preparation F

The efficacy of lipid preparation is investigated in a single-center,open label, ˜3 months trial in 8 elderly with impaired cognitiveperformance.

1 capsule containing 162 mg of lipid preparation F (containing 100 mgPS) is administered three (3) times daily with meals.

Memory functions of the subjects are tested using computerized cognitiveassessment tool and Rey-AVLT procedure essentially as described inExample 2.

Results

Lipid preparation F tends to improve memory recall, memory recognition,attention, concentration, learning and spatial short term memory only toa minor extent following ˜3 months treatment period. The improvement ofall parameters tested is lower than the improvement following ˜3treatment months with any of the lipid preparations A (Example 2), B, Cand D.

TABLE 5 Fatty acid content

 and

w/w %* LA conjugated to w/w % Linolenic acid w/w % LA conjugated to w/w% Linolenic acid PS/w/w % DHA conjugated to PS/w/w % PS/w/w % EPAconjugated to PS/w/w % % Soy PS % Marine PS conjugated to PS DHAconjugated to PS conjugated to PS EPA conjugated to PS Source SourcePreparation A   1:1 0.08:1  2.5:1  0.2:1 25 75 Preparation A1 0.94:10.09:1 2.36:1 0.23:1 25 75 Preparation A2 1.38:1 0.13:1 3.46:1 0.32:1 2575 Preparation B <0.02:1  ≦0.02:1  ≦0.05:1  ≦0.05:1  0 100 Preparation C0.09:1 0.01:1 0.23:1 0.02:1 3 97 Preparation D  3.6:1  0.3:1  9.4:1 0.8:1 55 45 Preparation E >100:1  ≧10:1 ≧100:1  ≧10:1 100 0 PreparationF  8.9:1  0.7:1  23:1  1.8:1 75 25 *Weight percent of a fatty acidconjugated to PS relative to weight of the total fatty acids conjugatedto PS

indicates data missing or illegible when filed

TABLE 6 Phospholipid content (w/w %) of Preparations A-F PS PC PI PE PAPreparation A 50 0-1 0-3 3 8 Preparation A1 54 0-1 0-3 3.5 9 PreparationA2 54 0-1 0-3 3.5 9 Preparation B 44 0-1 0-3 4 7.5 Preparation C 45 0-10-3 4 8 Preparation D 57 0-1 0-3 2.5 9 Preparation E 67 0-1 0-3 1 11Preparation F 62 0-1 0-3 2 10

TABLE 7 Fatty acid conjugated to PS (weight percent from total fattyacids conjugated to PS) C14 C16 C16:1 C18 C18:1 C18:2 C18:3 C20:1 C20:5C22:6 Preparation A 1.5 24.7 1.7 3.1 16.5 20.5 1.7 1.5 8.0 20.6Preparation A1 1.6 20.6 0.9 2.7 15.1 20.7 2.0 1.6 8.8 22.0 PreparationA2 1.4 19.9 0.9 3.0 15.7 26.2 2.4 1.3 7.6 19.0 Preparation B 2.2 29.82.6 2.2 18.0 ≦0.5 ≦0.5 2.2 12.0 31.0 Preparation C 2.1 29.1 2.5 2.3 17.82.7 0.2 2.1 11.5 29.6 Preparation D 0.8 19.9 0.9 4.0 15.1 39.6 3.2 0.84.2 10.9 Preparation E ≦0.5 14.5 ≦0.5 5.0 13.5 61.0 5.0 ≦0.5 ≦0.5 <0.5Preparation F 0.4 17.3 0.5 4.5 14.3 50 4.1 0.4 2.2 5.6

TABLE 8 Ratio between omega 6 fatty acids and omega 3 fatty acids on PSOmega 6/omega 3 ratio Preparation A 0.7 Preparation A1 0.63 PreparationA2 0.9 Preparation B ≦0.01 Preparation C 0.06 Preparation D 2.2Preparation E ≧10 Preparation F 4.2

TABLE 9 Fatty acid content* and Source of Preparations G-N w/w %* LAconjugated to w/w % Linolenic acid w/w % LA conjugated to w/w %Linolenic acid PS/w/w % DHA conjugated to PS/w/w % PS/w/w % EPAconjugated to PS/w/w % % Soy PS % Marine PS conjugated to PS DHAconjugated to PS conjugated to PS EPA conjugated to PS Source SourcePreparation G   3:1 0.24:1 7.7:1 0.6:1 50 50 Preparation H  2.4:1  0.2:16.3:1 0.5:1 45 55 Preparation I   2:1 0.16:1  5:1 0.4:1 40 60Preparation J  1.6:1 0.13:1 4.2:1 0.3:1 35 65 Preparation K  1.3:1 0.1:1 3.3:1 0.27:1  30 70 Preparation L 0.75:1 0.06 1.9:1 0.16:1  20 80Preparation M 0.53:1 0.04:1 1.4:1 0.1:1 15 85 Preparation N 0.33:10.03:1 0.9:1 0.07:1  10 90 *Weight percent of a fatty acid conjugated toPS relative to weight of the total fatty acids conjugated to PS

1. A preparation comprising a non-mammalian derived mixture of serineglycerophospholipid conjugates, wherein the mixture comprises (a)linoleic acid (C18:2) conjugated to PS and (b) DHA conjugated to PS inwhich mixture the w/w % of (a)/the w/w % of (b) is from about 0.09 toabout 3.6.
 2. A preparation according to claim 1, wherein the serineglycerophospholipid constitutes at least 10% w/w of the preparation. 3.A preparation according to claim 2, wherein the serineglycerophospholipid constitutes at least 20% w/w of the preparation. 4.A preparation according to claim 3, wherein the serineglycerophospholipid constitutes at least 40% w/w of the preparation. 5.A preparation according to claim 4, wherein the serineglycerophospholipid constitutes at least 50% w/w of the preparation. 6.A preparation according to claim 5, wherein the serineglycerophospholipid constitutes at least 54% w/w of the preparation. 7.A preparation according to claims 1 further comprising (c) linolenicacid (C18:3) conjugated to PS and (d) DHA conjugated to PS wherein thew/w% of (c)/w/w % of (d) is from about 0.01 to about 0.3.
 8. Apreparation according to claim 7 further comprising (e) linoleic acid(C18:2) conjugated to PS and (f) EPA conjugated to PS wherein the w/w %of (e)/w/w % of (f) is from about 0.23 to about 9.4.
 9. A preparationaccording to claim 8 further comprising (g) linolenic acid (C18:3)conjugated to PS and (h) EPA conjugated to PS wherein the w/w % of(g)/w/w % of (h) is from about 0.02 to about 0.8.
 10. A method ofimproving a condition in a subject suffering from a cognitive disease ordisorder comprising administering to a subject in need thereof apreparation according to claim
 1. 11. A method according to claim 10,wherein the cognitive disease or disorder is selected from the groupconsisting of Attention Deficit Disorder, Attention DeficitHyperactivity Disorder, dyslexia, age-associated memory impairment andlearning disorders, amnesia, mild cognitive impairment, cognitivelyimpaired disease, Parkinson's disease, pre-dementia syndrome, dementia,age related cognitive decline, cognitive deterioration, moderate mentalimpairment, mental deterioration due to aging, conditions that influencethe intensity of brain waves and/or brain glucose utilization, stress,anxiety, depression, behavior disorders, concentration and attentionimpairment, mood deterioration, general cognitive and mental well being,neurodegenerative disorders, hormonal disorders and any combinationthereof.
 12. A nutritional, pharmaceutical or nutraceutical composition,or a functional food comprising the preparation of claim
 1. 13. A methodfor improving a condition in a subject suffering from a cognitivedisease or disorder which comprises administering to the subject aneffective amount of the nutritional, pharmaceutical or nutraceuticalcomposition or the functional food of claim
 12. 14. A method accordingto claim 13, wherein the cognitive disease or disorder is selected fromthe group consisting of Attention Deficit Disorder, Attention DeficitHyperactivity Disorder, dyslexia, age-associated memory impairment andlearning disorders, amnesia, mild cognitive impairment, cognitivelyimpaired non-demented, pre-Alzheimer's disease, Alzheimer's disease,Parkinson's disease, pre-dementia syndrome, dementia, age relatedcognitive decline, cognitive deterioration, moderate mental impairment,mental deterioration due to ageing, conditions that influence theintensity of brain waves and/or brain glucose utilization, stress,anxiety, depression, behavior disorders, concentration and attentionimpairment, mood deterioration, general cognitive and mental well being,neurodegenerative disorders, hormonal disorders and any combinationthereof.
 15. (canceled)
 16. (canceled)
 17. (canceled)
 18. (canceled)